An experimental Axsome Therapeutics drug for treatment-resistant depression has fallen short of the main goal of a late-stage test. But the company says the pill is showing enough promise to warrant trying another Phase 3 study.
Axsome (NASDAQ: AXSM) tested its drug, AXS-05, in patients with major depressive disorder who had previously failed to respond to treatment with antidepressants. The study, which enrolled 312 patients, compared the Axsome drug to the antidepressant bupropion. Patients were evaluated according to the Montgomery-Åsberg depression rating scale, a diagnostic questionnaire used to measure the severity of depression episodes. Axsome reported Monday that patients treated with its drug failed to show a statistically significant improvement in depression scores after six weeks, which was the main goal of the study.
Despite falling short of that goal, Axsome says its drug worked more quickly than bupropion to produce a therapeutic effect, and it points to better marks on the study’s secondary endpoints. Axsome’s twice-daily pill did better than bupropion at improving patient depression scores at weeks one and two of the study. Also, after six weeks the Axsome drug averaged better scores than its comparator.
Shares of Axsome opened Monday at $54 apiece, down more than 14 percent from Friday’s closing price.
The Axsome drug is a proprietary combination of dextromethorphan and buproprion. Dextromethorphan is a cough suppressant that works by blocking signals in the brain that trigger a cough reflex. In AXS-05, dextromethorphan is intended to block NMDA receptors, which play a role in depression. The buproprion component of AXS-05 is intended to improve how much of the drug circulates in the body and is available to provide a therapeutic effect.
Speaking on an Axsome conference call, Maurizio Fava, the chief of psychiatry at Massachusetts General Hospital (MGH), noted that the buproprion arm of the study was essentially a 12-week trial because all patients were treated for six weeks before being randomly assigned to either the AXS-05 group or the buproprion group. The dose of buproprion in the AXS-05 group was also lower. Fava said both factors may account for the drug falling short in the clinical trial, and could be addressed by increasing the sample size.
Fava, who also directs the MGH Research Institute’s clinical research division and serves as associate dean for clinical and translational research at Harvard Medical School, said that the results support further study of AXS-05. As many as half of those who visit his hospital don’t respond to one or two treatments, making it important to find new drugs for such patients, including ones that, like Axsome’s, can be taken by mouth, he said. Also, patients treated with the Axsome drug showed improvement in cognition—attention, concentration, memory—compared to those who received buproprion. Fava called that finding “very impressive” because antidepressants typically don’t improve such brain activities.
“About 30 to 40 percent of patients who respond to antidepressants continue to have cognitive impairment,” he said. “So having a treatment that is more effective than monotherapy antidepressant in addressing cognition, that’s very clinically meaningful. It happens to be statistically significant, too, at week six.”
Axsome did not respond to Xconomy’s inquiry about whether Fava has any disclosures regarding connections to the company.
According to an investor presentation, the group treated with the Axsome drug had three adverse events: migraine, overdose, and thoughts of suicide. The most common side effects reported were dizziness and nausea. The drug was well tolerated by patients and there were no reports of psychosis, weight gain, or sexual dysfunction—side effects that are associated with other depression treatments.
Based on the Phase 3 results, Axsome CEO Herriot Tabuteau said the company plans to start a second late-stage test for AXS-05 in treatment-resistant depression in the third quarter of this year. Results from the first Phase 3 test, including details about the secondary endpoints, will be submitted for presentation at upcoming medical meetings and for publication.
The results announced Monday are separate from Axsome’s tests of the AXS-05 as a treatment for major depressive disorder. Last December, the company reported positive Phase 3 results in that indication. Tabuteau said Monday that the company plans a regulatory submission to the FDA for that program in the fourth quarter of this year.
AXS-05 is also in Phase 2/3 testing as a potential treatment for agitation in Alzheimer’s disease patients. Axsome expects to report preliminary data from that study early in the second quarter of this year.